The cannabinoid agonist Win55,212-2 inhibits calcium channels by receptor-mediated and direct pathways in cultured rat hippocampal neurons.
The effects of the cannabinoid receptor agonist Win55,212 on Ca2+ channels were studied in rat hippocampal neurons grown in primary culture. Win55,212-2 inhibited whole-cell Ba2+ currents through Ca2+ channels by both CB1 receptor-mediated and direct mechanisms. The concentration dependent inhibition of the current showed two clear phases, a high-affinity receptor-mediated phase (IC50=14+/-2 nM) that was stereoselective and sensitive to a CB1 receptor antagonist, 300 nM SR141716, and a non-saturating phase that was neither stereoselective nor inhibited by SR141716. These concentration-dependent effects were paralleled by Win55212-induced inhibition of glutamatergic synaptic transmission. Win55,212-2 (100 nM) inhibited both omega-agatoxin IVA- and omega-conotoxin GVIA-sensitive currents. Thus, activation of cannabinoid receptors inhibits N- and P/Q-type Ca2+ channels. Activation of cannabinoid receptors inhibited only a fraction of the whole-cell Ca2+ channel current (17+/-2%) even though more than half of the whole-cell Ba2+ current was carried by N- and P/Q-type Ca2+ channels. Concentrations of agonist greater than 1 microM inhibited Ca2+ channels directly.
Shen
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Department of Pharmacology, University of Minnesota Medical School, 3-249 Millard Hall, 435 Delaware St. SE, Minneapolis, MN 55455, USA.
Thayer
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SA
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D048588:Benzoxazines; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002186:Cannabinoids / Q000378:metabolism*; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists*
D000700:Analgesics; D048588:Benzoxazines; D002121:Calcium Channel Blockers; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone